The control of mammalian cell replication is one of the major unsolved problems in biology. Tissue culture techniques, which have contributed significantly to the understanding of enzyme induction, promise to be equally valuable in studying cell replication. This proposal represents the merging of two existing projects, and will employ cultured cells to investigate the regulation of mammalian cell replication and enzyme induction and the role cyclic nucleotides play in these processes. I have recently shown that in two lines of cultured tumor cells, HTC and RLC cells, the adenylate cyclase yields cAMP yields protein kinase yields effect system differs in several ways from that in liver, the tissue of origin of these lines. Using high resolution acrylamide gel electrophoresis we have also shown a positive correlation between the extent of F1-histone phosphorylation (presumably by protein kinase) and the rate of HTC cell replication. I have outlined a series of experiments which will employ cultured cells to investigate further the relationship of cyclic nucleotides to cell replication and enzyme induction. These studies are grouped into three categories: 1) Further characterization and purification of the protein kinases (regulatory and catalytic units) of liver and three hepatic-derived cell lines (HTC, RLC, and H4-II-E); 2) Studies which exploit differences in protein kinases in cell lines to establish the role these proteins play in processes such as enzyme induction and cell replication (comparing the effects of cAMP and cGMP on both these processes and attempting to restore "lost" functions of the cells); 3) Investigations of the relationship of histone phosphorylation (and regulation of such) to cell replication. If histone phosphorylation regulates cell replication and if the enzyme responsible for this is subject to modulation by cyclic nucleotides, we might expect to gain greater insight into the means of controlling abnormal cell replication or malignancy.